This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to novel phenylene analogs of some of the known prostaglandins, i.e. prostaglandin E.sub.1 (PGE.sub.1), prostaglandin F.sub.1.alpha. (PGF.sub.1.alpha.), and prostaglandin A.sub.1 (PGA.sub.1).
Each of the above-mentioned known prostaglandins is a derivative of prostanoic acid which has the following structure and atom numbering: ##STR2## A systematic name for prostanoic acid is 7-[(2.beta.-octyl)cyclopent-1.alpha.-yl]heptanoic acid.
PGE.sub.1 has the following structure: ##STR3##
PGF.sub.1.alpha. has the following structure: ##STR4##
PGA.sub.1 has the following structure: ##STR5##
The prostaglandin formulas mentioned above each have several centers of asymmetry. As drawn, formulas II-IV each represents the particular optically active form of the prostaglandin obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, and human seminal plasma, or by reduction or dehydration of a prostaglandin so obtained; see, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. The mirror image of each formula represents a molecule of the enantiomer of that prostaglandin. The racemic form of the prostaglandin consists of equal numbers of two types of molecules, one represented by one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin. See Nature 212, 38 (1866) for discussion of the stereochemistry of the prostaglandins.
In the formulas II-IV above, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. See, for example, C-8 and C-11 in the PGE.sub.1 formula above. Likewise, the side-chain hydroxy at C-15 in the formulas above is in alpha (S) configuration. See R. S. Cahn, Journal of Chemical Education 41, 116 (1964) for a discussion of S and R configurations. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.
PGE.sub.1, PGF.sub.1.alpha., and PGA.sub.1 and their esters, and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic blood pressure lowering in anesthetized pentolinium-treated rats with indwelling aortic and right heart cannulas; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pigileum, rabbit duodenum, or gerbil colon; decrease of blood platelet adhesiveness, and inhibition of blood platelet aggregation.
Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, for example, mice, rats, rabbits, and monkeys, as is well known in the art.
Previously, certain phenylene-containing prostaglandin analogs were disclosed. See U.S. Pat. No. 3,933,897, 3,933,898, and 3,944,595, for a group of phenyleneoxa compounds having a divalent phenylene moiety ##STR6## and an oxa oxygen (--O--) in the carboxyl-terminated side chain. See Belgian Pat. No. 820,003, Derwent Farmdoc 22475W for related compounds which are distinguishable from prostaglandins in that they are 11-deoxy compounds.